Recent economic advances and lifestyle changes have been accompanied by great changes in dietary habit. In particular, busy people of today are becoming overweight and obese due to high-calorie diets and insufficient exercise. According to a report of the World Health Organization (WHO), more than one billion adults are overweight worldwide, among them over three million are clinically diagnosed with severe obesity, and 250,000 people in Europe and 2.5 million people worldwide died of overweight- or obesity-related diseases every year (World Health Organization, Global Strategy on Diet, Physical Activity and Health, 2004).
Overweight and obesity increase blood pressure and blood cholesterol level, thus becoming a cause of various diseases including heart disease, diabetes, arthritis, etc., or aggravating the diseases. Further, overweight and obesity are some of the main causes that increase the risk of diseases such as arteriosclerosis, hypertension, hyperlipidemia, and heart disease in children and adolescents as well as in adults.
As such, obesity is now recognized as a serious disease prevalent all over the world and is a cause of various diseases. However, since obesity is believed to be overcome by self-help efforts, obesity patients are being evaluated as people with low self-control. Nevertheless, obesity is not readily curable because it is a complicated disease closely associated with appetite control and a mechanism of action for energy metabolism. Accordingly, for obesity treatment, it is required that both an individual effort for appetite control and treatment of an abnormal mechanism of action for energy metabolism be conducted concurrently. In this regard, there has been a need for the development of a drug capable of treating the abnormal mechanism of action.
As a result of the above effort, anti-obesity drugs such as Rimonabant® (Sanofi-Aventis), Sibutramin® (Abbott), Contrave® (Takeda), Orlista® (Roche), etc., have been developed. However, these drugs had drawbacks such as fatal adverse reactions or little efficacy in treating obesity. For example, Rimonabant® shows an adverse reaction of central nervous system disorder, Sibutramin® and Contrave® show adverse cardiovascular effects, and Orlista® shows an effect of body weight decrease of only about 4 kg after one year of administration. Accordingly, there appears to be no sure anti-obesity drug to be safely prescribed to obesity patients.
As such, active research has been conducted to develop a new pharmaceutical drug to resolve the problems in the conventional anti-obesity drugs, and recently, keen attention has been paid to glucagon derivatives. Glucagon is secreted by the pancreas when the blood glucose level falls low due to, for example, drug treatment, diseases, hormones, or enzyme deficiency. Glucagon signals the liver to break down glycogen to glucose and raise the blood glucose level to return to its normal level. Furthermore, glucagon has been reported to have an anti-obesity effect, in addition to the effect of raising the blood glucose level, by suppressing appetite and activating hormone-sensitive lipase in fat cells, thereby promoting fat decomposition.
Glucagon-like peptide-1 (hereinafter, referred to as ‘GLP-1’), a glucagon derivative, is a substance under development as a drug to improve hyperglycemia in diabetic patients. GLP-1 has the functions of increasing insulin synthesis and promoting its secretion, inhibiting glucagon secretion, inhibiting gastric emptying, enhancing the use of glucose, and inhibiting food intake. Also, exendin-4, which is secreted by lizard venom and shows about 50% homology in amino acid sequence with GLP-1, is known to alleviate hyperglycemia in diabetes patients by activating the GLP-1 receptor. However, anti-obesity drugs containing GLP-1 or exendin-4 have been reported to have adverse effects of causing vomiting and nausea.
In this regard, as a GLP-1 alternative, oxyntomodulin, which can bind to both GLP-1 and glucagon peptides, has been highlighted. Oxyntomodulin is a peptide made from pre-glucagon, the precursor of glucagon, and has the same effects of GLP-1 such as inhibiting food intake, promoting satiety, and fat decomposition, thus raising its potential as an anti-obesity agent.
However, oxyntomodulin or its derivatives have a drawback in that they should be administered daily at a high dose due to their short in vivo half-lives and low efficacies.